Article Date: 6/1/2012

Higher Lucentis Dose in DME

Higher Lucentis Dose in DME

A 1 mg dose improves results.

■ An attention-getting ARVO presentation by Philip J. Ferrone, MD, and Jon Jonisch, MD, of Long Island Vitreoretinal Consultants, indicates that increasing the Lucentis dose for DME from 0.5 mg to 1 mg produces both better visual results and more normal macular volume over a two-year period.

In this investigator-sponsored, prospective, randomized clinical trial, the researchers reported that eyes with clinically significant DME secondary to diabetic retinopathy were randomized to one of two groups, 0.5 mg or 1.0 mg ranibizumab. During the first year, each patient received three monthly injections followed by injections on an every other month as-needed retreatment protocol. During the second year, patients were seen every month and received as-needed monthly injections of drug.

A 24-month analysis included 42 eyes of 42 patients (20 eyes in 0.5-mg group, and 22 eyes in 1.0-mg group). The two groups did not differ materially at baseline in age, sex, ETDRS letters, OCT central thickness/volume or blood pressure. The 1.0-mg group had a baseline ETDRS vision of 60.8 letters with a final vision of 71.2 letters at two years. The 0.5-mg group had a baseline ETDRS vision of 57.5 letters with a final vision of 64.5 letters at two years.

The 1.0-mg group had an average gain of 10.4 ETDRS letters as compared with 7.0 letters in the 0.5-mg group. The mean decrease of central foveal thickness achieved was 192 µm in the 1.0-mg group and 216 µm in the 0.5-mg group. There was a statistically significant difference between the groups with respect to final macular volume at two years, with the 0.5- mg group having a higher volume than the 1.0-mg group: 7.95 vs. 6.85.

In the 1.0-mg group, 27% of patients gained 15 or more ETDRS letters, compared to 15% of patients in the 0.5-mg group. The average number of injections in the 1.0-mg group was 12.0, as compared to 12.9 in the 0.5-mg group.

The researchers concluded that treatment of clinically significant DME with either 0.5 mg or 1.0 mg of ranibizumab resulted in a statistically significant improvement in visual acuity from baseline. There was a significant difference between the two dose groups across time for ETDRS visual acuity. The 1.0-mg dose group had improved resolution of macular edema versus the 0.5-mg ranibizumab group at two years. The number of injections did not differ significantly between the two groups.

OIG and CMS clash over Avastin reimbursement. The Office of the Inspector General (OIG), a division of HHS that exercises financial oversight over Medicare, wants a national payment policy for reimbursing Avastin. CMS is resisting this move. Recently announced two-year CATT study data, which essentially showed equivalent effectiveness between Lucentis and Avastin in treating wet AMD, will almost certainly add fuel to this dispute.
At issue is the fact that the cost of a Lucentis injection averages about 40 times the cost of an Avastin injection, which is placing a major financial burden on Medicare amounting to approximately $1 billion a year. Currently, Avastin is reimbursed under Medicare Part B but there is a local coverage determination rather than a national payment policy. There is a national payment policy for Lucentis.
OIG also asked CMS to conduct an educational campaign to further acquaint providers with the clinical and payment issues related to the two drugs. CMS has agreed to do this.

Needle size in intravitreal injections. In a survey of patient preference conducted by researchers from Vienna and presented at ARVO, 193 patients receiving intravitreal injections were randomized to a 27-g needle or a 30-g needle. Following the administration of standard topical anesthesia and the injection, the patients were asked to grade their level of pain using two accepted measures of pain scoring.
The results showed no significant difference in reported pain from either the 27-g needle or the 30-g needle, though females, older patients and individuals with a previous history of intravitreal injections said they felt overall higher levels of pain. In a separate questionnaire, the doctors giving the injections showed an overall preference for the 30-g needle.

Retinal Adhesion May Be Key to CNV

Indiana U. researchers put forth a new theory.

■ An accident in which a donated human retina from an eye bank was severely shaken and damaged during shipping inspired Abbas Shirinifard, PhD, of the University of Indiana's Biocomplexity Institute, to begin a series of simulations. Upon examination of the eye, Dr. Shirinifard and a microscopist had found that regions of the retina with invading blood vessels had separated from their underlying membrane, while regions that had stayed attached showed much less invasion, suggesting that adhesion might be an essential but overlooked mechanism in maintaining the retina's structure.

Using an open-source modeling software program called Compu Cell3D, the team began extending existing simulations to study the effects of adhesion defects.

“The simulations showed that reduced adhesion in the retina could indeed lead to its invasion by blood vessels,” Dr. Shirinifard said. “But the complex structure of the retina meant that many types of adhesion could be important: the three most prominent being between the pigmented retinal cells and Bruch's membrane, between adjacent pigmented retinal cells, and between pigmented retinal cells and the overlying photoreceptors.”

Those variables, the team realized, could be independent of one another or interact in complex ways, and knowing that the rate and type of progression of the disease varies greatly from patient to patient, they needed to use a high-performance computer to examine many examples of each adhesion combination.

“We were able to model the interactions of different degrees of impairment of each type of adhesion and the variation from case to case,” Dr. Shirinifard said. “Amazingly, these simulations were able to replicate the complex spectrum of CNV seen in the clinic.”

Simulations of adhesion defects caused by reduced adhesion between pigmented retinal cells and Bruch's membrane — the type of CNV typical of aging — produced a pattern and frequency of invasion agreeing with that in the clinic. Similarly, reduced adhesion between neighboring pigmented retinal cells, typical of inflammation due to severe infection, produced a pattern of invasion agreeing with that seen in young adults.

By combining thousands of simulations, Dr. Shirinifard was able to produce maps that related defects in each type of adhesion to the risk of each type of invasion. In turn, he could show that cell adhesion is key to keeping blood vessels out of the retina and that combination defects in the different types of adhesion are sufficient to determine the probability, pattern and rate of progression of CNV.

The full results of this work were published recently in PLoS Computational Biology, and while the team has yet to move toward developing new CNV therapies, the work should have great significance in the search for better therapies, according to Biocomplexity Institute Director James Alexander Glazier, a co-author on the paper.

“Hundreds of millions of dollars are spent annually to develop drugs and treatment approaches based on the two commonly hypothesized CNV initiation and progression mechanisms,” he said. “Because the current work shows that neither hypothesized mechanism is an important cause of CNV, that money and effort are extremely unlikely to improve outcomes for patients.”

Instead of what he chracterized as “barking up the wrong tree,” he said that a search for therapies that restore normal adhesion in the eye is much more likely to produce effective treatments. In addition, the detailed agreement between simulation and clinical observations suggests that new approaches to measuring adhesion in patients would allow much more accurate predictions of the prognosis for individual patients.

In the April 2012 issue of Retinal Physician, the authors of the article “Spontaneous Intraocular Hemorrhage in Metastatic Testicular Cancer” were incompletely listed. In addition to Daniel A. Chruscicki, MD, the case study was also authored by Stephanie Sutton, MS, and Elizabeth Sutton, MS. We apologize for this omission.

Pain Relief After Intravitreal Injection

Study compares four protocols.

■ A retrospective study conducted by researcher Stephen Winkler and Dan Alter, MD, PhD, evaluated the effectiveness of four different protocols that had been used at a single clinic at different times to alleviate pain following intravitreal injection.

All patients initially received either one drop of tetracaine or lidocaine followed by a single drop of povidone iodine 10% PI-10%). Following dilation, the patients were given five drops of topical anesthetic (tetracaine or lidocaine 2%). A lid speculum was placed and another drop of PI-10% was given. The injection was then given and one of four post-injection washouts (gatifloxacin, gatifloxacin + prednisolone, eyewash, lidocaine 2% topical solution) was performed. Patients were then asked to rate their pain on a 1-10 scale immediately after washout. Twenty fours hours postinjection, patients were asked rate their average pain score over the course of the day on the same scale.

Of the 161 eyes injected, 38 were placed into group 1 (gatifloxacin only), 35 into group 2 (gatifloxacin + prednisolone), 38 into group 3 (eyewash) and 50 into group 4 (lidocaine). The average pains scores initially following the washouts were 4.31 (SD 2.63), 4.31 (SD 2.16), 6.54 (SD 1.83), and 2.70 (SD 1.80) for groups 1 through 4 respectively. The average pain scores over 24 hours post-injection were 5.54 (SD 2.97), 4.80 (SD 2.42) 2.54 (SD 2.22) for groups 1, 2, and 4 respectively. Note: due to the unacceptable pain score reported by group 3 patients immediately following injection, a lidocaine 2% washout was initiated for 26 of the patients post-eyewash. Their initial pain score was 3.5 (SD 1.6) following lidocaine washout.

The researchers pointed to the fact that the number of intravitreal injections is growing exponentially and will only increase with the advent of new medications, indications for injections, and the aging population.

They asserted that “efficient delivery of anesthesia and effective pain control will become increasingly important to maintain patient comfort and compliance. A simple protocol that maintains efficiency but minimizes pain and post-injection complications will be crucial.”

They concluded that the protocol involving topical lidocaine along with a lidocaine washout not only avoids a subconjunctival injection but also demonstrates pain control, both initially and over the course of 24 hours following the intravitreal injection.

This research was presented at the recent ARVO meeting.

Iluvien approved in UK, Austria. Alimera Sciences said its Iluvien implant for the treatment of DME has been approved in both the UK and Austria following a European regulatory body's ruling allowing approval on a country-by-country basis. The FDA has requested additional trials of the implant before it will reconsider granting US approval for Iluvien.
Five more European countries could approve Iluvien sometime in the next year. These include France, Germany, Italy, Spain and Portugal.

Oraya study reduces anti-VEGF injections. Oraya Therapeutics said the INTREPID clinical trial of radiation therapy has met its primary endpoint of reduction in anti-VEGF injections for patients with wet AMD, though the company provided no further details. The INTREPID study is the first sham-controlled double-masked trial to evaluate the effectiveness and safety of a one-time radiation therapy in conjunction with as-needed anti-VEGF injections for the treatment of wet AMD. Preliminary result analyses found no indication of radiation-related adverse events at the one-year trial end point. Detailed results from the INTREPID study will be presented during the Euretina Congress in Milan in September.
All 230 patients in the study had previously received at least three anti-VEGF injections in the prior year and required further anti-VEGF treatment. Within two weeks following injection, one third of the subjects received a sham exposure and the remainder received a radiation dose of either 16 or 24 Gy. They were then followed monthly and treated with anti-VEGF (Lucentis) as needed according to specified reinjection criteria. The multinational study included sites in Austria, Czech Republic, Germany, Italy and the United Kingdom. RP

Retinal Physician, Volume: 9 , Issue: June 2012, page(s): 6 - 12